Current perspectives on the immunosuppressive tumor microenvironment in hepatocellular carcinoma: challenges and opportunities

Lu, Chen; Rong, Dawei; Zhang, Betty; Zheng, Wubin; Wang, Xuehao; Chen, Ziyi; Tang, Weiwei

doi:10.1186/s12943-019-1047-6

Molecular Cancer

Table 1 A Summary of Molecule Target Therapies in HCC

From: Current perspectives on the immunosuppressive tumor microenvironment in hepatocellular carcinoma: challenges and opportunities

Molecule	Target cell	Therapeutic setting	Major effects	Reference
CCR2	TAMs	CCR2 antagonist	Inhibits the recruitment of inflammatory monocytes, infiltration and M2-polarisation of TAMs	[34]
CCR2	TAMs	Anti-CCR2	Promotes epithelial‑to‑mesenchymal transition by upregulating matrix metalloproteinase‑2	[35]
CCR2	TAMs	CCR2 monoclonal antibody	Inhibits recruitment of monocytes	[36]
CSF-1	TAMs	CSF-1 receptor antagonist	Reprograms polarization of TAMs	[37]
IL-6	TAMs	Anti-IL-6	Blocks downstream effect of TAM products	[38]
IL-6	MDSCs	Anti-IL-6	IL-6 expression levels strongly correlate with an MDSC phenotype and chemotherapy response in HCC patients	[44]
chemokine (C-C motif) ligand 26	MDSCs	Blockade of chemokine (C-C motif) ligand 26	Knockdown of chemokine (C-C motif) ligand 26 in cancer cells profoundly reduces MDSC recruitment, angiogenesis, and tumor growth	[45]
SSAO	MDSCs	SSAO inhibitors	May have an anti-tumor effect on HCC by inhibiting recruitment of CD11b⁺ and Gr-1⁺ cells and hindering angiogenesis	[46]
STAT3	MDSCs	Anti-STAT3	Inhibiting STAT3 can enhance the clinical efficacy of CAR-T cells in LM through modulation of L-MDSC	[47]
CCRK	MDSCs	Anti-CCRK	Hepatic CCRK induction in transgenic mice stimulates mTORC1-dependent G-csf expression to enhance polymorphonuclear MDSCs recruitment and tumorigenicity in HCC	[48]
CCL9/CCR1	MDSCs	Blockade of CCL9/CCR1	CCL9 secreted by splenic macrophages induces a CCR1‑dependent accumulation of MDSCs in the spleen in a murine H22 hepatoma model	[49]
ENTPD2/CD39L1	MDSCs	Blockade of ENTPD2/CD39L1	Hypoxia induces the expression of ENTPD2 on cancer cells leading to elevated extracellular 5'-AMP, which promotes the maintenance of MDSCs by preventing their differentiation in HCC	[50]
PD-L1	MDSCs	PD-1 monoclonal antibody	PD-L1⁺ MDSCs could be used as a new biomarker of HCC	[51]
IL-18/TLR2	MDSCs	Blockade of IL-18/TLR2	IL-18 administration was sufficient to induce accumulation of MDSC, whereas hepatocyte-specific silencing of IL-18 in TLR2(-/-) mice decreased the proportion of MDSC	[52]
TGF-β/Axl/CXCL5	TANs	Blockade of TGF-β/Axl/CXCL5	The synergy of TGF-β and Axl induces CXCL5 secretion, causing the infiltration of neutrophils into HCC tissue.	[72]
cortisol	TANs	Inhibition of cortisol	increased cortisol production and TAN/TAM infiltration as primary factors in the gender disparity of HCC development in both fish and human	[73]
CXCR2/CXCL1	TANs	Blockade of CXCR2/CXCL1	The CXCR2-CXCL1 axis can regulate neutrophil infiltration into HCC tumor tissues and might represent a useful target for anti-HCC therapies	[74]
CXCL17	TANs	Anti-CXCL17	CXCL17 expression was associated with more CD68 and less CD4 cell infiltration	[75]
CXCR6	TANs	Anti-CXCR6	Human HCC samples expressing high levels of CXCR6 contained an increased number of CD66⁺ neutrophils and microvessels	[76]
miRNA-21	CAFs	MiRNA-21 inhibitor	High level of serum exosomal miRNA-21 was correlated with greater activation of CAFs and higher vessel density in HCC patients	[84]
CD24	CAFs	Anti-CD24	HGF and IL6 secreted by CAFs promoted the stemness properties of CD24⁺ HCC cells through the phosphorylation of STAT3	[85]
LOXL2	CAFs	Anti--LOXL2	The secreted LOXL2 promotes fibronectin production, MMP9 and CXCL12 expression and BMDCs recruitment to assist pre-metastatic niche formation	[86]
PD-L1/IL6/STAT3	CAFs	Blockade of PD-L1/IL6/STAT3	HCC-CAFs regulate the survival, activation, and function of neutrophils within HCC through an IL6-STAT3-PDL1 signaling cascade	[87]
IL6/STAT3	CAFs	blockade of IL6/STAT3	IL-6 secreted by CAFs promotes stem cell-like properties in HCC cells by enhancing STAT3/Notch signaling	[88]
Keratin 19	CAFs	Anti-Keratin 19	Keratin 19 expression in HCC is regulated by Fibroblast-Derived HGF via a MET-ERK1/2-AP1 and SP1 Axis.	[89]
LSD1	CAFs	Anti-LSD1	LSD1 Stimulates Cancer-Associated Fibroblasts to Drive Notch3-Dependent Self-Renewal of Liver Cancer Stem-like Cells	[90]
PD-1	Tregs	PD-1 monoclonal antibody	The ratio of CD4⁺CD127⁺ PD-1^- T effector cells to CD4⁺Foxp3⁺PD-1⁺ Tregs was significantly increased following treatment with sorafenib	[114]
PD-1	Tregs	PD-1 monoclonal antibody	Sunitinib-mediated tumoricidal effect and Treg suppression synergized with antibody-mediated blockade of PD-1 to powerfully suppress tumor growth and activate anti-tumor immunity	[115]
PD-1	Tregs	PD-1 monoclonal antibody	Sorafenib treatment enhanced functions of tumor-specific effector T cells as well as relieved PD-1-mediated intrinsic and Treg-mediated non-cell-autonomous inhibitions in tumor microenvironment	[116]
CTLA4	Tregs	CTLA4 monoclonal antibody	Leptin inhibited Treg activation and function in vitro, demonstrated by lower expression of TGF-β, IL-10, CTLA4 and GITR in Tregs	[117]
CTLA4	Tregs	CTLA4 monoclonal antibody	Tumor-induced regulatory DC subset suppresses antitumor immune response through CTLA-4-dependent IL-10 and IDO production	[118]
TIM3	Tregs	TIM3 monoclonal antibody	Antibodies against TIM3 restore responses of HCC-derived T cells to tumor antigens, and combinations of the antibodies have additive effects	[119]
Lnc-Tim3	Tregs	Anti-Lnc-Tim3	Lnc-Tim3 promotes T cell exhaustion, a phenotype which is correlated with compromised anti-tumor immunity	[120]
TIM3	Tregs	TIM3 monoclonal antibody	TIM3 -1516 G/T polymorphisms may affect the prognosis of HBV-related HCC and may be new predictors of prognosis for HCC patients	[121]
TIM3	Tregs	TIM3 monoclonal antibody	-1516G/T polymorphism in the promoter region of TIM3 gene may affect the disease susceptibility and HCC traits associated with HBV infection	[122]
GITR	Tregs	GITR monoclonal antibody	Agonistic targeting of GITR can enhance functionality of HCC TIL and may therefore be a promising strategy for single or combinatorial immunotherapy in HCC	[123]
GITR	Tregs	GITR monoclonal antibody	GITR-ligation and anti-CTLA-4 mAb can improve the antitumor immunity by abrogating Ti-Treg mediated suppression in HCC.	[124]
ICOS	Tregs	ICOS monoclonal antibody	Regulatory T cells, especially ICOS⁺ FOXP3⁺ regulatory T cells, are increased in the HCCmicroenvironment and predict reduced survival	[125]
OX40	Tregs	OX40 monoclonal antibody	OX40 expression in HCC is associated with a distinct immune microenvironment, specific mutation signature, and poor prognosis	[126]
LAG3	Tregs	LAG3 monoclonal antibody	Antibodies against LAG3 restore responses of HCC-derived T cells to tumor antigens, and combinations of the antibodies have additive effects	[119]

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